Prostate cancer is a common form of cancer in men worldwide, and in 2008 was the sixth leading cause of cancer death. Initial presentation of prostate cancer is generally androgen-dependent, such that androgen-deprivation therapy, for example through chemical or surgical castration provides a therapeutic benefit. Over time, however, changes to the cancer result in the emergence of androgen-independent cells and relapse and progression of the disease. Various additional therapeutic agents are now available that are focused on the treatment of androgen-independent prostate cancer. Among these therapeutic agents is enzalutamide (previously known as MDV3100), an androgen-receptor antagonist that blocks the androgen receptor. Another drug, ARN-509, operates through competitive AR inhibition, impairing nuclear translocation of the AR, and AR binding to androgen-response elements of DNA.
Not all CRPC is responsive to androgen-receptor antagonists, including enzalutamide, and resistance can develop after a period of treatment. In the case of enzalutamide, this resistance may arise in at least some instances due to a splice-variant that lacks the ligand binding site of the androgen receptor with which enzalutamide interacts.
Bispecific antisense oligonucleotides are known, for example, from U.S. Pat. No. 7,928,082, which is incorporated herein by reference. Bispecific siRNA oligomers are disclosed in U.S. Pat. No. 7,973,017, which is incorporated herein by reference.
One particular bispecific antisense oligonucleotide is known as OGX-225, a second generation antisense oligonucleotide under development by OncoGenex Pharmaceuticals, Inc. OGX-225 has the structure
SEQ ID NO: 15′-CAGCAGCCGCAGCCCGGCTC-3′.
In specific known formulations, SEQ ID NO. 1 is in the form of a 20 base phosphorothioate oligonucleotide; 5-10-5 MOE gapmer, 19 sodium salt having the sequence:
DNA (P-thio)(SEQ ID NO: 2)5′-MeCAGMeCAGMeCMeCGMeCAGMeCMeCMeCGGMeCMeUMeC-3'Where:                The underlined nucleosides (G, MeC, A and MeU) denote 2′-O-(2-methoxyethyl) (2′-MOE) modifications of the ribonucleosides guanosine, 5-methylcytidine, adenosine and 5-methyluridine (MeU=T).        G, MeC, and A represent the deoxyribonucleosides 2′-deoxyguanosine, 2′-deoxy-5-methylcytidine, and 2′-deoxyadenosine.        The internucleotide linkages are phosphorothioate diesters (nonadecasodium salt).        